Rare coding variants and X-linked loci associated with age at menarche

Kathryn L. Lunetta, Felix R. Day, Patrick Sulem, Katherine S. Ruth, Joyce Y. Tung, David A. Hinds, Toñu Esko, Cathy E. Elks, Elisabeth Altmaier, Chunyan He, Jennifer E. Huffman, Evelin Mihailov, Eleonora Porcu, Antonietta Robino, Lynda M. Rose, Ursula M. Schick, Lisette Stolk, Alexander Teumer, Deborah J. Thompson, Michela Traglia & 101 others Carol A. Wang, Laura M. Yerges-Armstrong, Antonis C. Antoniou, Caterina Barbieri, Andrea D. Coviello, Francesco Cucca, Ellen W. Demerath, Alison M. Dunning, Ilaria Gandin, Megan L. Grove, Daniel F. Gudbjartsson, Lynne J. Hocking, Albert Hofman, Jinyan Huang, Rebecca D. Jackson, David Karasik, Jennifer Kriebel, Ethan M. Lange, Leslie A. Lange, Claudia Langenberg, Xin Li, Jian'an Luan, Reedik Mägi, Alanna C. Morrison, Sandosh Padmanabhan, Ailith Pirie, Ozren Polasek, David Porteous, Alex P. Reiner, Fernando Rivadeneira, Igor Rudan, Cinzia F. Sala, David Schlessinger, Robert A. Scott, Doris Stöckl, Jenny A. Visser, Uwe Völker, Diego Vozzi, James G. Wilson, Marek Zygmunt, Eric Boerwinkle, Julie E. Buring, Laura Crisponi, Douglas F. Easton, Caroline Hayward, Frank B. Hu, Simin Liu, Andres Metspalu, Craig E. Pennell, Paul M. Ridker, Konstantin Strauch, Elizabeth A. Streeten, Daniela Toniolo, André G. Uitterlinden, Sheila Ulivi, Henry Völzke, Nicholas J. Wareham, Melissa Wellons, Nora Franceschini, Daniel I. Chasman, Unnur Thorsteinsdottir, Anna Murray, Kari Stefansson, Joanne M. Murabito, Ken K. Ong, John R B Perry, Nita G. Forouhi, Nicola D. Kerrison, Stephen J. Sharp, Matt Sims, Inês Barroso, Panos Deloukas, Mark I. McCarthy, Larraitz Arriola, Beverley Balkau, Aurelio Barricarte, Heiner Boeing, Paul W. Franks, Carlos Gonzalez, Sara Grioni, Rudolf Kaaks, Timothy J. Key, Carmen Navarro, Peter M. Nilsson, Kim Overvad, Domenico Palli, Salvatore Panico, J. Ramón Quirós, Olov Rolandsson, Carlotta Sacerdote, María José Sánchez, Nadia Slimani, Anne Tjonneland, Rosario Tumino, Daphne L. Van Der A, Yvonne T. Van Der Schouw, Elio Riboli, Blair H. Smith, Archie Campbell, Ian J. Deary, Andrew M. McIntosh

    Research output: Contribution to journalArticle

    17 Citations (Scopus)

    Abstract

    More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼ 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P-8). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10-13) and FAAH2 (rs5914101, P=4.9 × 10-10). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10-11), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.

    Original languageEnglish (US)
    Article number7756
    JournalNature Communications
    Volume6
    DOIs
    StatePublished - Aug 4 2015

    Fingerprint

    Menarche
    chromosomes
    loci
    mutations
    genes
    coding
    Genes
    X Chromosome
    Chromosomes
    homeostasis
    genome
    fatty acids
    amides
    Mutation
    Hypogonadism
    Penetrance
    Genome-Wide Association Study
    RNA Interference
    low frequencies
    proteins

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)
    • Chemistry(all)
    • Physics and Astronomy(all)

    Cite this

    Lunetta, K. L., Day, F. R., Sulem, P., Ruth, K. S., Tung, J. Y., Hinds, D. A., ... McIntosh, A. M. (2015). Rare coding variants and X-linked loci associated with age at menarche. Nature Communications, 6, [7756]. https://doi.org/10.1038/ncomms8756

    Rare coding variants and X-linked loci associated with age at menarche. / Lunetta, Kathryn L.; Day, Felix R.; Sulem, Patrick; Ruth, Katherine S.; Tung, Joyce Y.; Hinds, David A.; Esko, Toñu; Elks, Cathy E.; Altmaier, Elisabeth; He, Chunyan; Huffman, Jennifer E.; Mihailov, Evelin; Porcu, Eleonora; Robino, Antonietta; Rose, Lynda M.; Schick, Ursula M.; Stolk, Lisette; Teumer, Alexander; Thompson, Deborah J.; Traglia, Michela; Wang, Carol A.; Yerges-Armstrong, Laura M.; Antoniou, Antonis C.; Barbieri, Caterina; Coviello, Andrea D.; Cucca, Francesco; Demerath, Ellen W.; Dunning, Alison M.; Gandin, Ilaria; Grove, Megan L.; Gudbjartsson, Daniel F.; Hocking, Lynne J.; Hofman, Albert; Huang, Jinyan; Jackson, Rebecca D.; Karasik, David; Kriebel, Jennifer; Lange, Ethan M.; Lange, Leslie A.; Langenberg, Claudia; Li, Xin; Luan, Jian'an; Mägi, Reedik; Morrison, Alanna C.; Padmanabhan, Sandosh; Pirie, Ailith; Polasek, Ozren; Porteous, David; Reiner, Alex P.; Rivadeneira, Fernando; Rudan, Igor; Sala, Cinzia F.; Schlessinger, David; Scott, Robert A.; Stöckl, Doris; Visser, Jenny A.; Völker, Uwe; Vozzi, Diego; Wilson, James G.; Zygmunt, Marek; Boerwinkle, Eric; Buring, Julie E.; Crisponi, Laura; Easton, Douglas F.; Hayward, Caroline; Hu, Frank B.; Liu, Simin; Metspalu, Andres; Pennell, Craig E.; Ridker, Paul M.; Strauch, Konstantin; Streeten, Elizabeth A.; Toniolo, Daniela; Uitterlinden, André G.; Ulivi, Sheila; Völzke, Henry; Wareham, Nicholas J.; Wellons, Melissa; Franceschini, Nora; Chasman, Daniel I.; Thorsteinsdottir, Unnur; Murray, Anna; Stefansson, Kari; Murabito, Joanne M.; Ong, Ken K.; Perry, John R B; Forouhi, Nita G.; Kerrison, Nicola D.; Sharp, Stephen J.; Sims, Matt; Barroso, Inês; Deloukas, Panos; McCarthy, Mark I.; Arriola, Larraitz; Balkau, Beverley; Barricarte, Aurelio; Boeing, Heiner; Franks, Paul W.; Gonzalez, Carlos; Grioni, Sara; Kaaks, Rudolf; Key, Timothy J.; Navarro, Carmen; Nilsson, Peter M.; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Quirós, J. Ramón; Rolandsson, Olov; Sacerdote, Carlotta; Sánchez, María José; Slimani, Nadia; Tjonneland, Anne; Tumino, Rosario; Van Der A, Daphne L.; Van Der Schouw, Yvonne T.; Riboli, Elio; Smith, Blair H.; Campbell, Archie; Deary, Ian J.; McIntosh, Andrew M.

    In: Nature Communications, Vol. 6, 7756, 04.08.2015.

    Research output: Contribution to journalArticle

    Lunetta, KL, Day, FR, Sulem, P, Ruth, KS, Tung, JY, Hinds, DA, Esko, T, Elks, CE, Altmaier, E, He, C, Huffman, JE, Mihailov, E, Porcu, E, Robino, A, Rose, LM, Schick, UM, Stolk, L, Teumer, A, Thompson, DJ, Traglia, M, Wang, CA, Yerges-Armstrong, LM, Antoniou, AC, Barbieri, C, Coviello, AD, Cucca, F, Demerath, EW, Dunning, AM, Gandin, I, Grove, ML, Gudbjartsson, DF, Hocking, LJ, Hofman, A, Huang, J, Jackson, RD, Karasik, D, Kriebel, J, Lange, EM, Lange, LA, Langenberg, C, Li, X, Luan, J, Mägi, R, Morrison, AC, Padmanabhan, S, Pirie, A, Polasek, O, Porteous, D, Reiner, AP, Rivadeneira, F, Rudan, I, Sala, CF, Schlessinger, D, Scott, RA, Stöckl, D, Visser, JA, Völker, U, Vozzi, D, Wilson, JG, Zygmunt, M, Boerwinkle, E, Buring, JE, Crisponi, L, Easton, DF, Hayward, C, Hu, FB, Liu, S, Metspalu, A, Pennell, CE, Ridker, PM, Strauch, K, Streeten, EA, Toniolo, D, Uitterlinden, AG, Ulivi, S, Völzke, H, Wareham, NJ, Wellons, M, Franceschini, N, Chasman, DI, Thorsteinsdottir, U, Murray, A, Stefansson, K, Murabito, JM, Ong, KK, Perry, JRB, Forouhi, NG, Kerrison, ND, Sharp, SJ, Sims, M, Barroso, I, Deloukas, P, McCarthy, MI, Arriola, L, Balkau, B, Barricarte, A, Boeing, H, Franks, PW, Gonzalez, C, Grioni, S, Kaaks, R, Key, TJ, Navarro, C, Nilsson, PM, Overvad, K, Palli, D, Panico, S, Quirós, JR, Rolandsson, O, Sacerdote, C, Sánchez, MJ, Slimani, N, Tjonneland, A, Tumino, R, Van Der A, DL, Van Der Schouw, YT, Riboli, E, Smith, BH, Campbell, A, Deary, IJ & McIntosh, AM 2015, 'Rare coding variants and X-linked loci associated with age at menarche', Nature Communications, vol. 6, 7756. https://doi.org/10.1038/ncomms8756
    Lunetta KL, Day FR, Sulem P, Ruth KS, Tung JY, Hinds DA et al. Rare coding variants and X-linked loci associated with age at menarche. Nature Communications. 2015 Aug 4;6. 7756. https://doi.org/10.1038/ncomms8756
    Lunetta, Kathryn L. ; Day, Felix R. ; Sulem, Patrick ; Ruth, Katherine S. ; Tung, Joyce Y. ; Hinds, David A. ; Esko, Toñu ; Elks, Cathy E. ; Altmaier, Elisabeth ; He, Chunyan ; Huffman, Jennifer E. ; Mihailov, Evelin ; Porcu, Eleonora ; Robino, Antonietta ; Rose, Lynda M. ; Schick, Ursula M. ; Stolk, Lisette ; Teumer, Alexander ; Thompson, Deborah J. ; Traglia, Michela ; Wang, Carol A. ; Yerges-Armstrong, Laura M. ; Antoniou, Antonis C. ; Barbieri, Caterina ; Coviello, Andrea D. ; Cucca, Francesco ; Demerath, Ellen W. ; Dunning, Alison M. ; Gandin, Ilaria ; Grove, Megan L. ; Gudbjartsson, Daniel F. ; Hocking, Lynne J. ; Hofman, Albert ; Huang, Jinyan ; Jackson, Rebecca D. ; Karasik, David ; Kriebel, Jennifer ; Lange, Ethan M. ; Lange, Leslie A. ; Langenberg, Claudia ; Li, Xin ; Luan, Jian'an ; Mägi, Reedik ; Morrison, Alanna C. ; Padmanabhan, Sandosh ; Pirie, Ailith ; Polasek, Ozren ; Porteous, David ; Reiner, Alex P. ; Rivadeneira, Fernando ; Rudan, Igor ; Sala, Cinzia F. ; Schlessinger, David ; Scott, Robert A. ; Stöckl, Doris ; Visser, Jenny A. ; Völker, Uwe ; Vozzi, Diego ; Wilson, James G. ; Zygmunt, Marek ; Boerwinkle, Eric ; Buring, Julie E. ; Crisponi, Laura ; Easton, Douglas F. ; Hayward, Caroline ; Hu, Frank B. ; Liu, Simin ; Metspalu, Andres ; Pennell, Craig E. ; Ridker, Paul M. ; Strauch, Konstantin ; Streeten, Elizabeth A. ; Toniolo, Daniela ; Uitterlinden, André G. ; Ulivi, Sheila ; Völzke, Henry ; Wareham, Nicholas J. ; Wellons, Melissa ; Franceschini, Nora ; Chasman, Daniel I. ; Thorsteinsdottir, Unnur ; Murray, Anna ; Stefansson, Kari ; Murabito, Joanne M. ; Ong, Ken K. ; Perry, John R B ; Forouhi, Nita G. ; Kerrison, Nicola D. ; Sharp, Stephen J. ; Sims, Matt ; Barroso, Inês ; Deloukas, Panos ; McCarthy, Mark I. ; Arriola, Larraitz ; Balkau, Beverley ; Barricarte, Aurelio ; Boeing, Heiner ; Franks, Paul W. ; Gonzalez, Carlos ; Grioni, Sara ; Kaaks, Rudolf ; Key, Timothy J. ; Navarro, Carmen ; Nilsson, Peter M. ; Overvad, Kim ; Palli, Domenico ; Panico, Salvatore ; Quirós, J. Ramón ; Rolandsson, Olov ; Sacerdote, Carlotta ; Sánchez, María José ; Slimani, Nadia ; Tjonneland, Anne ; Tumino, Rosario ; Van Der A, Daphne L. ; Van Der Schouw, Yvonne T. ; Riboli, Elio ; Smith, Blair H. ; Campbell, Archie ; Deary, Ian J. ; McIntosh, Andrew M. / Rare coding variants and X-linked loci associated with age at menarche. In: Nature Communications. 2015 ; Vol. 6.
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    T1 - Rare coding variants and X-linked loci associated with age at menarche

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    AU - Day, Felix R.

    AU - Sulem, Patrick

    AU - Ruth, Katherine S.

    AU - Tung, Joyce Y.

    AU - Hinds, David A.

    AU - Esko, Toñu

    AU - Elks, Cathy E.

    AU - Altmaier, Elisabeth

    AU - He, Chunyan

    AU - Huffman, Jennifer E.

    AU - Mihailov, Evelin

    AU - Porcu, Eleonora

    AU - Robino, Antonietta

    AU - Rose, Lynda M.

    AU - Schick, Ursula M.

    AU - Stolk, Lisette

    AU - Teumer, Alexander

    AU - Thompson, Deborah J.

    AU - Traglia, Michela

    AU - Wang, Carol A.

    AU - Yerges-Armstrong, Laura M.

    AU - Antoniou, Antonis C.

    AU - Barbieri, Caterina

    AU - Coviello, Andrea D.

    AU - Cucca, Francesco

    AU - Demerath, Ellen W.

    AU - Dunning, Alison M.

    AU - Gandin, Ilaria

    AU - Grove, Megan L.

    AU - Gudbjartsson, Daniel F.

    AU - Hocking, Lynne J.

    AU - Hofman, Albert

    AU - Huang, Jinyan

    AU - Jackson, Rebecca D.

    AU - Karasik, David

    AU - Kriebel, Jennifer

    AU - Lange, Ethan M.

    AU - Lange, Leslie A.

    AU - Langenberg, Claudia

    AU - Li, Xin

    AU - Luan, Jian'an

    AU - Mägi, Reedik

    AU - Morrison, Alanna C.

    AU - Padmanabhan, Sandosh

    AU - Pirie, Ailith

    AU - Polasek, Ozren

    AU - Porteous, David

    AU - Reiner, Alex P.

    AU - Rivadeneira, Fernando

    AU - Rudan, Igor

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    AU - Schlessinger, David

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    AU - Visser, Jenny A.

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    AU - Vozzi, Diego

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    AU - Hu, Frank B.

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    AU - Metspalu, Andres

    AU - Pennell, Craig E.

    AU - Ridker, Paul M.

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    AU - Streeten, Elizabeth A.

    AU - Toniolo, Daniela

    AU - Uitterlinden, André G.

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    AU - Völzke, Henry

    AU - Wareham, Nicholas J.

    AU - Wellons, Melissa

    AU - Franceschini, Nora

    AU - Chasman, Daniel I.

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    AU - Murray, Anna

    AU - Stefansson, Kari

    AU - Murabito, Joanne M.

    AU - Ong, Ken K.

    AU - Perry, John R B

    AU - Forouhi, Nita G.

    AU - Kerrison, Nicola D.

    AU - Sharp, Stephen J.

    AU - Sims, Matt

    AU - Barroso, Inês

    AU - Deloukas, Panos

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    AU - Arriola, Larraitz

    AU - Balkau, Beverley

    AU - Barricarte, Aurelio

    AU - Boeing, Heiner

    AU - Franks, Paul W.

    AU - Gonzalez, Carlos

    AU - Grioni, Sara

    AU - Kaaks, Rudolf

    AU - Key, Timothy J.

    AU - Navarro, Carmen

    AU - Nilsson, Peter M.

    AU - Overvad, Kim

    AU - Palli, Domenico

    AU - Panico, Salvatore

    AU - Quirós, J. Ramón

    AU - Rolandsson, Olov

    AU - Sacerdote, Carlotta

    AU - Sánchez, María José

    AU - Slimani, Nadia

    AU - Tjonneland, Anne

    AU - Tumino, Rosario

    AU - Van Der A, Daphne L.

    AU - Van Der Schouw, Yvonne T.

    AU - Riboli, Elio

    AU - Smith, Blair H.

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    N2 - More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼ 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P-8). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10-13) and FAAH2 (rs5914101, P=4.9 × 10-10). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10-11), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.

    AB - More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼ 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P-8). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10-13) and FAAH2 (rs5914101, P=4.9 × 10-10). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10-11), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.

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